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New Horizons 2008: International Conference on ME/CFS Biomedical Research

New Horizons 2008: International Conference on ME/CFS Biomedical Research

Hosted and organised by ME Research UK, and co-sponsored by the Irish ME Trust, the New Horizons 2008: International Conference on ME/CFS Biomedical Research took place on 6th May 2008 at the Wellcome Trust Conference Centre on the Genome Campus at Hinxton near Cambridge, UK, an outstanding custom-designed venue designed to attract the world’s leading scientists to debate issues at the forefront of new scientific discovery.

Building on the success of last year’s conference at Heriot-Watt University, Edinburgh (read the report here), the day brought together researchers from around the world, healthcare professionals, representatives from local support groups, and delegates from ME/CFS charities. The full day’s programme consisted of invited keynote lectures from scientists from Scotland, England, USA, Canada, Belgium, Sweden and Australia.

The media coverage of the conference was far greater than in previous years — thanks to Bob Ward and Sarah Emberson who volunteered their professional PR services to “energise media awareness” — and media coverage included the following:

Order your copy of the 4-DVD set (morning and afternoon) of the presentations by contacting our headquarters; the cost is £5 (including P&P within the UK) for the four-DVD set. You can pay by cheque (made payable to “ME Research UK”), and orders can also be taken by credit/dedit card over the phone. (You can also send a set as a gift direct to your GP, consultant or other healthcare professional; please contact us for information.)

Roger Jefcoate CBE

Delegates were welcomed by Sue Waddle who was chairing the conference with Prof. Nancy Klimas and Bob McRae. The conference proper was opened formally by Roger Jefcoate CBE, co-founder of ME Research UK with Dr Vance Spence and Bob McRae, and a Patron of the charity. Roger explained that he felt greatly privileged to be welcoming delegates to such a prestigious event, and went on to describe how he came to be involved in ME and in funding research into the illness. For all of his working life, he has actively promoted technology for disabled people, including developing the world’s first remote control system for severely disabled people at the National Spinal Injuries Centre, Stoke Mandeville Hospital, a system that is still freely available through the National Health Service, with thousands of happy users and carers nationwide. In 1983, he started a trust to fund adapted computers for severely disabled people, some of whom were housebound or even bedbound with ME; and in 1998 he was asked by Dr Vance Spence to fund a vital laser Doppler scanner for the ongoing biomedical research at Dundee University with Professor Jill Belch and Dr Faisel Khan. At nearly £30,000, this donation for the laser Doppler scanner remains the largest ever donation his charity has given. He continued:

As you all well know, people with ME suffer grievously, often with little support or understanding, sometimes isolated and ignored by the very institutions that should be helping — such as the National Health Service and the Benefits Agency. Indeed, it is a matter of continuing astonishment to me that for so severe an illness, biomedical research is so underfunded, including by agencies such as the Medical Research Council which should be the first port of call. ME Research UK has become a beacon of hope for many patients, some of whom — I know from personal experience — have lived for many years in this sea of darkness and despair. It is heartening to see, therefore, the range of experts who have volunteered to come and share with us their efforts to explore the biomedical basis of the illness. A report to the Chief Medical Officer of England in 2002 said that a programme of research on all aspects of ME/CFS was urgently needed, and that improvement of health and social care was an urgent challenge. We hope that this conference will concentrate minds on scientific aspects of this illness.

Nancy Klimas and Sue Waddle

The first keynote lecture was by Prof. Nancy Klimas (pictured left, with Sue Waddle) of the University of Miami School of Medicine and the Miami VA Medical Center, who directs the UM/VAMC Gulf War and Chronic Fatigue Syndrome Research Center, which focuses on better understanding of the neuro-immune-endocrine interactions in both these complex disorders. Her presentation was entitled “Clinical Aspects of ME/CFS”, and her key initial emphasis was on the need to move beyond “case definitional” issues of ME and CFS towards assessing patients (sub-grouping) on the basis of clinical tests and symptom clusters as outlined in the Canadian Consensus Definition of 2003, of which she was a co-author. In her view, the post-exertional nature of symptoms are key, but it is also important to identify sleep anomalies, pain and autonomic dysfunctions which can be prevalent.

After reviewing the epidemiology — suggesting that there could be one million people with CFSin the USA — she described a model for the development of the illness. The model postulates a genetic predisposition (supported by past work on HLA DR haplotypes), which encounters a triggering event or infection, leading to the production of immune, endocrine or neuroendocrine mediators, resulting in a poor health outcome and persistence of illness. As she explained, chronic immune activation has long been thought to be a component of CFS, and T-lymphocytes appear to be chronically activated. Indeed, CD8 cells in patients typically demonstrate an increase in activation markers (CD38, HLA-DR) and a reduction in CD8 suppressor cells. Also, there is evidence that the homeostasis between the cell-mediated or T helper (Th1) immune response and the humoral (Th2) immune response is disrupted in CFS, as well as evidence of increased pro-inflammatory cytokine expression (TNF-a, IL1, IL6).

Prof. Klimas reviewed the evidence for viral persistence and reactivation (e.g., enterovirus, HHV6 and EBV), and then discussed the evidence for endocrine dysfunction, such as reduced cortisol output via several mechanisms (though many possible confounding factors such as deconditioning, sleep, and medication make final conclusions difficult). As regards autonomic dysfunction in ME/CFS, this has been measured as neurally mediated hypotension, orthostatic hypotension, parasympathetic dysfunction, sympathetic overactivation — and she indicated that Dr Julia Newton’s presentation later in the day would go into these aspects in greater depth.

Gene expression microarray data has become a highly productive tool for better understanding CFS research, and Prof. Klimas described recent studies, including the differential expression of 35 genes for T-cell activation, neuronal and mitochondrial regulatory abnormalities. Again, pre-post exercise challenge gene studies have indicated differences in genes that regulate ion transport and intracellular cell functions, and it may be that evaluation of gene expression profiles will allow for pathophysiologic subgrouping of patients. Advances in the field should result in targeted therapies to impact immune function, HPA axis regulation and persistent viral reactivation in CFS patients.

The next keynote lecture was given by Dr Jo Nijs, an academic physiotherapist with special interest in chronic pain and ME/CFS who works at the Vrije Universiteit Brussel, Belgium, and the University College of Antwerp where he is Head of the Division of Musculoskeletal Physiotherapy.

Dr Nijs gave an overview of his recent paper on “Intracellular immune dysfunction in ME/CFS: state-of-the-art and therapeutic implications” (published in Expert Opin Ther Targets 2008; 12:281-289), in which he examined the accumulating evidence in support of intracellular immune dysfunction in the illness. From an in-depth review of the scientific literature, he and his colleagues concluded that proteolytic cleavage of the native RNase L enzyme is characteristic of dysregulation of intracellular immunity in people with ME/CFS, although the origin of the dysregulation is unexplained at present. There is increasing evidence for upregulation of various aspects of the 2-5A synthetase/RNase L pathway and for immune cell apoptosis in ME/CFS. The dysregulation and upregulation of the 2-5A synthetase/RNase L pathway in ME/CFS are not just epiphenomena: evidence in support of their clinical importance has been provided. Conflicting data of the functioning of the PKR enzyme in blood cells of ME/CFS patients have been reported, possibly reflecting various stages of the illness or distinct subgroups. Intracellular immune impairments are related to poor exercise performance, but future research should reveal the exact nature of this association.

Jo Nijs

Dr Nijs explained that it seems plausible that decreased natural killer cell function, the presence of infections and intracellular immune dysfunctions are interrelated parts of the ME/CFS pathophysiology, but these potential interactions still need to be unravelled. More insight into the exact nature of these interactions is likely to come from well-designed drug treatment studies. Particularly needed are studies examining the effects of drug treatment in conjunction with exercise interventions. Since post-exertional malaise is one of the major problems with exercise therapy in ME/CFS, drugs might be able to diminish the side effects of exercise interventions, possibly leading to improved compliance and effectiveness.

In the final presentation of the first session, Dr Gregor Purdie, a general practitioner and GP Adviser to NHS Dumfries and Galloway, described service development and patient pathways from the perspective of the practising clinician. Dr Purdie has been actively involved in moves towards setting up a Scottish Clinical Network on ME/CFS, the outcome being “responsive, empathetic, patient-centred care of high quality delivered by clinicians who have kept abreast of the latest research, with seamless working between primary, secondary and tertiary care”. As regards achieving such a network, he stressed that we need to ask ourselves who is to do this, when and how. At present in the pyramid of care most of the burden is taken up up by ME/CFS and other voluntary organisations at the base, but ideally it would be dispersed throughout the pyramid in a multidisciplinary approach involving consultants, primary care and healthcare support staff, with Centres of Excellence as a key aspect of the overall mix.

In the following session, Dr Byron Hyde (pictured), from Nightingale Research Foundation, Ottawa, Canada, outlined some of his conclusions from his years seeing ME and CFS patients. He explained that unlike physicians in other countries, he operates inside the Canadian healthcare system within which he can order any blood, urine or tissue test free of charge for any Canadian citizen, including MRI and SPECT imaging.

Byron Hyde

His talk began by outlining myalgic encephalomyelitis which he described not as a syndrome but a disease process causing a diffuse measurable pathophysiological injury of the brain (CNS). He showed SPECT scans from his practice, and observed that they showed evidence of brain injuries. As regards the question of the triggers or causes of ME, he discussed epidemics, particularly the 1984-1992 Ontario ME epidemic period during which enterovirus seemed to have an important role, concluding that it would be scientifically inexcusable not to consider that the enterovirus group was responsible for the diffuse brain damage noted in acute onset ME patients. As regards ME patients across the board, Dr Hyde’s view is that the cause of the illness could be anything (virus, immunisation, physical trauma) that can cause a chronic diffuse injury of the CNS, hence the need for brain SPECT and brain PET imaging in evaluation.

He highlighted sleep dysfunction as a prominent part of the illness. Indeed, when his Nightingale clinic in Ottawa studied 53 consecutive patients, only one had normal sleep; most patients had insufficient sleep or were blocked in stage 1 and 2 non-restorative sleep, 31 had no stage 3 sleep, and 43 had insufficient or no stage 4 sleep. In a significant minority of these patients, mean oxygen saturation fell to low levels during the night. A copy of Dr Hyde’s presentation to the conference can be found at the Nightingale Clinic website.

Dr Derek Enlander (Mount Sinai Medical School, New York; and New York ME/CFS Center, New York, USA) gave the next presentation which described his treatment of ME/CFS patients with a complex intramuscular injection, oral l-cystine, glutathione, methylcobalalmin, follinic acid and electrolytes. Based on treatment of approximately 800 patients over 15 years, he explained that he has developed a protocol which has helped 65% of patients, based on SF36 and other test criteria. Although the protocol originally started with weekly intramuscular kutapressin, results indicated that only approx 30% of patients were helped, so Dr Enlander has persisted over the past decade to better these results, adding (in stages) intramuscular magnesium sulphate, calphosan, methylcobalamin, folic acid, glutathione, trace zinc and molybdenum. This protocol seemed to be in line with a theory of a methylation cycle defect in ME/CFS. Although glutathione is poorly absorbed, Dr Enlander surmised that if glutathione was given by intramuscular and oral routes, a certain percentage will enter the circulation, so the protocol was extended to include daily oral capsules of glutathione and l-cystine, and daily oral capsules containing a range of vitamins. The addition of a potassium, sodium, magnesium and calcium combination seems to help muscle weakness and pain.

The role of the ME/CFS Clinic in the UK as regards clinical assessment and service delivery was described in a presentation by Dr Gavin Spickett (Consultant Clinical Immunologist, Royal Victoria Infirmary, Newcastle upon Tyne). There are now 13 Clinical Network Co-ordinating Centres (CNCC in the UK) and Dr Spickett is Clinical Champion for Northern ME/CFSCNCC in Newcastle.

His presentation discussed the care pathways adopted in clinical practice in the North of England — recently described in the Nice Guideline 2007 — including the key role of medical assessment which aims to undertake a detailed clinical evaluation (after GPs have already performed routine tests, including pre-screening bloods) to identify alternative diagnoses that may present with fatigue to ensure that patients receive appropriate treatment for these. Evidence from studies in the clinics has shown that experienced clinicians are able to make alternative diagnoses in a significant percentage of patients referred from primary care with suspected ME/CFS, and that education programmes directed at primary care, as well as strict referral guidelines, do not seem to have reduced the prevalence of alternative diagnoses. For example, an audit of the Newcastle clinic in 1998 showed that 17% of patients referred could be given alternative diagnoses, and a recent re-audit in 2007 showed that in the first three years of the new service ME/CFS was confirmed in only 56% of referrals, with the remainder consisting of alternative diagnoses (28%), sleep apnoea (9%), and depression and anxiety (7%). He explained that with the advent of the NICE Guideline 2007 and its encouragement of earlier diagnosis, the proportion of alternative diagnoses might be expected to rise.

Gavin Spickett and Malcolm Hooper

Dr Spickett (pictured left, with Prof. Malcolm Hooper) emphasised that it is essential both for the subsequent therapeutic intervention and for the development of research cohorts that, in the absence of specific confirmatory tests, a clear diagnosis, according to International Criteria can be made for each patient. For those with a diagnosis of ME/CFS, the NICE-based management approaches consist of interventions based around models used for the chronic pain team (biopsychosocial model) including activity-based approaches (pacing, graded exercise, sleep hygiene), lifestyle management, CBT, and physio and occupational therapy. An important aspect of the work of the clinical service is the provision of help with benefits, and the provision of letters to the Department of Work and Pensions to support the maintenance of benefits for patients attending the clinic.

Dr Spickett presented preliminary data on outcomes of the management approach above for a small number of patients (n=7 or 8) using the Minimum Dataset; these showed mixed results on the Chalder fatigue score (42%/42%/14% improved/unchanged/worsened, respectively), pain score (28%/28%/28%, respectively), and SF36 quality of life score (0/28%/57%). As he explained, the numbers available for analysis are very small as yet, but in the future there will be a need to identify those patients not benefiting from the interventions on offer, who might need to be offered a different therapeutic approach.

The morning session was brought to a close by Prof. Julia Newton (Senior Lecturer, Institute of Cellular Medicine, Newcastle University) who spoke of her work on the autonomic nervous system and its dysfunction in ME/CFS. Prof. Newton explained how the autonomic nervous system is responsible for subconscious activities that occur in the human body, such as respiration, bladder and bowel function. It is also integral to the maintenance of cardiovascular functions such as maintenance of heart rate and blood pressure. Autonomic dysfunction and particularly low blood pressure (hypotension) are a frequent finding in people with the symptom of ‘fatigue’ generally, and her programme of research is directed towards understanding the role of autonomic dysfunction and developing interventions that target autonomic nervous system abnormalities.

Julia Newton and Bob McRae

She explained to a rapt audience that her research group has recently shown that 89% of those with ME/CFS experience symptoms on standing (orthostatic intolerance) and autonomic nervous system symptoms are frequently present in those with ME/CFS, the degree of which correlates with fatigue severity and is comparable to the symptom burden seen in a range of fatigue-associated chronic diseases (click here for a more exhaustive discussion of this work). Again, her studies examining haemodynamic responses to standing have shown that 27% (n=63) of ME/CFS patients have Positional Orthostatic Tachycardia Syndrome, and that cardiovascular parameters correlate with increasing fatigue. Recent preliminary results from a series of MRI scans in her unit have shown impaired proton removal from muscle during exercise in 16 patients with ME/CFS compared with matched controls, leading to the hypothesis that fatigue arises due to impaired pH run off from muscle during exercise, which is influenced either entirely or at least in part by the degree of autonomic dysfunction. As Julia explained in questions chaired by Bob McRae (pictured), research is now focusing on techniques to help patients with their autonomic symptoms, and one of these — orthostatic (tilt) training — is to be further assessed for ME/CFS patients; it might be that a (self-managed) tilt training program could be helpful symptomatically. Prof. Newton has recently received a large grant from ME Research UK to continue her important investigations on ME/CFS patients from the Newcastle clinic over the next two years.

The afternoon session began with an overview of the Whittemore Peterson Institute for NeuroImmune Disease, University of Nevada, by Dr Dan Peterson one of the co-founders, who also discussed some of the work currently underway or planned. The aim of the Institute is to be a comprehensive medical research facility devoted to patients with neuro-immune diseases such as ME/CFS, atypical multiple sclerosis, fibromyalgia, and other similarly presenting illnesses which account for billions in lost wages and increased healthcare costs yet receive relatively little attention or funding at the National Institutes of Health or the CDC. At present, the institute is under construction within the Center for Molecular Medicine on the campus of the University of Nevada, Reno, School of Medicine, and is scheduled to open formally in late summer 2010. This $70 million project brings basic researchers, clinical doctors and patients together to facilitate the exchange of new ideas and better communication.

Since its inception, the Institute has focused on research into the pathogenesis and aetiology of a subset of ME/CFS patients manifesting primarily neurological symptoms and concomitant laboratory abnormalities of the innate immune system. Additionally, translational studies have been instituted with respect to techniques to determine functionality and to explore promising therapeutic agents. In addition, as ME/CFS is a significant contributor to the financial burden, as well as functional disability, of the society at large, new approaches with respect to patient management are being encouraged and a structure to implement these patient-centred cost-effective approaches are being designed and implemented.

Dan Peterson

Dr Peterson (pictured) explained that disability carriers, as well as pharmaceutical companies, are seeking objective endpoints to determine the extent of disability and measure improvement in patients undergoing therapeutic strategies. Exercise tolerance testing with expired gas exchange has been widely published as a technique that is useful diagnostically, as well as for establishing therapeutic endpoints. A recent study done in collaboration with the University of the Pacific documented significant changes in a unique fashion in a sequential exercise tolerance test performed over a two-day interval. Additional studies to reproduce this finding and determine utility in therapeutic trials are currently being planned.

A subset of patients severely affected with ME/CFS with evidence of viral reactivation has been documented to demonstrate a gamma T-cell clonal rearrangement. Studies are currently underway to determine the monoclonality and antigen specificity of this unusual T-cell rearrangement, as well as intensive studies into the possible role of viruses in development of neoplastic disorders in a subset of chronically affected ME/CFS patients. Again, perturbations of the RNase L/2-5A synthetase antiviral pathway have been widely reported in a subset of patients, and RNase L studies are currently underway to further characterise this previously described abnormality and its significance to symptom development in people with ME/CFS.

Collaborative studies are ongoing, utilising a standardised viral array with the goal of identifying potentially treatable subsets of patients with a common virally induced aetiology that may be amenable to specific antiviral therapy. Cytokines have widely been implicated as mediators of symptomatology, both in the CNS and peripherally in patients suffering from ME/CFS. Dr Peterson explained that large-scale studies will be carried out to explore the presence of a variety of cytokines and functionality in patients and a large number of controls to further characterise potential patterns that may be useful diagnostically and potentially therapeutically. Recently, the specialised field of informatics has been utilised to analyse and manage complex inter-relationships involving multiple variables longitudinally; a model for applying informatics to mine data and reset the paradigm for ME/CFS has been proposed.

Dr Faisel Khan (The Institute of Cardiovascular Research, University of Dundee) described how his keynote lecture represented the work of a very active group which has uncovered a range of findings on ME/CFS patients in scientific papers from 2003 to 2007. These include increased oxidative stress, abnormally sensitive acetylcholine metabolism, and increased neutrophil apoptosis — specifically a larger proportion of dying (apoptotic) cells than in healthy subjects — consistent with an activated inflammatory process which is possibly the consequence of a past or present infection.

Dr Khan described his specific work on vascular function, and began by explaining the accumulating evidence that many patients have associated cardiovascular symptoms such as autonomic dysfunction, and attenuated heart rate and blood pressure regulation with increased vasomotor tone and loss of beat-to-beat heart rate control; such symptoms can contribute to destabilisation of blood pressure and orthostatic intolerance and, in the more severe CFS cases, a reduced cardiac output. Endothelial function is an important regulator of vascular function and is a well established marker of future cardiovascular events.

He explained how the group at Dundee had previously studied the vascular response in the forearm skin microcirculation to an endothelium-dependent vasodilator (acetylcholine, ACh) and found that CFS patients exhibited significantly enhanced vascular responses to ACh compared with control subjects. In a further study, they have demonstrated that the ACh sensitivity may be explained by prolonged action of the vascular response to ACh. Enhanced sensitivity to AChis not normally consistent with elements of endothelial dysfunction and increased cardiovascular risk. ACh sensitivity in CFS patients may be a consequence of a free radical attack on acetylcholinesterase expression on the vascular endothelium giving rise to a reduced expression of the enzyme, resulting in the prolongation of the ACh response.

Ken Chan, Neil Abbot and Faisel Khan

Dr Khan (pictured with his student Ken Chan and Dr Neil Abbot of ME Research UK) explained that his recent work concerned arterial stiffness, and the fact that the results showed arterial stiffness to be significantly elevated in CFS patients compared with control subjects (click here for a more exhaustive discussion of this work). The degree of “stiffness” was associated with levels of serum C-reactive protein (CRP), pointing to a role of low grade inflammation and oxidative stress. Thus the combination of augmented arterial stiffness and increased inflammation and oxidative stress may result in unfavourable haemodynamics. Increased arterial stiffness and inflammation might be regulated by levels of vitamin D, and the group are currently exploring the possible association between vitamin D and vascular function in these patients. In addition, the group is testing both focal endothelial function in the brachial artery and global endothelial function in smaller pre-resistance arteries, and also coronary flow reserve.

In his keynote lecture, Dr Jonathan Kerr (Department of Cellular and Molecular Medicine, St George’s University of London) described the background to the molecular studies that he has been conducting over the past four years. In previous work, he characterised gene expression in peripheral blood from 25 patients with ME/CFS, and 50 normal blood donors using the Affymetrix U133+2 microarray. Genes showing differential expression were further analysed using quantitative polymerase chain reaction in 55 patients with ME/CFS and 75 normal blood donors. Differential expression was confirmed for 88 genes, 85 of which were upregulated and three downregulated. Highly represented functions were haematological disease and function, immunological disease and function, cancer, cell death, immune response and infection. Clustering of data from patients with ME/CFS revealed seven distinct subtypes with distinct differences in Medical Outcomes Survey Short Form-36 scores, clinical phenotypes and severity.

Derek Enlander and Jonathan Kerr

In the most recent study which he described, the group determined for each CFS subtype the fold difference of each of the 88 CFS-associated genes compared with normal persons. Using a fold-difference cut-off of greater than 1.5, those genes that were differentially expressed in each CFS subtype were determined. As Dr Kerr (pictured right with Dr Enlander) explained, genomic analysis revealed some common (neurological, haematological, cancer) and some distinct (metabolic, endocrine, cardiovascular, immunological, inflammatory) disease associations among the subtypes. Subtypes 1, 2 and 7 were the most severe, and subtype 3 was the mildest. Clinical features of each subtype were as follows: subtype 1 (cognitive, musculoskeletal, sleep, anxiety/depression); subtype 2 (musculoskeletal, pain, anxiety/depression); subtype 3 (mild); subtype 4 (cognitive); subtype 5 (musculoskeletal, gastrointestinal); subtype 6 (postexertional); subtype 7 (pain, infectious, musculoskeletal, sleep, neurological, gastrointestinal, neurocognitive, anxiety/depression).

Dr Kerr explained that it was particularly interesting that there was evidence that the seven genomically derived subtypes were associated with distinct clinical syndromes, and that those which were most severe were also those with anxiety/depression, as would be expected in a disease with a biological basis. It remains to be determined what these subtypes represent, as they appear to be biologically meaningful, and to discover their natural history and possibilities for treatment. The team have already begun a study to develop a test based on human single nucleotide polymorphisms (SNPs) which could reliably determine subtype status in individuals.

Prof. Birgitta Evengård (Clinic Infectious Diseases, Umeå University, Sweden) gave the pentultimate lecture of the day on the role of the Swedish twin registry in searching for a biomarker for the illness. She described the ongoing work on characterising the epidemiological patterns and the role of genes and environment in the most severe phenotype of fatigue illnesses, the chronic fatigue syndrome (CFS), in a representative sample of the Swedish population. In the project, collection of epidemiological data, clinical and biological data, psychological and socio-demographic data are included, all evaluated with a gender perspective. The aim is to describe the prevalence of conditions characterised by chronic fatigue and their risk factors in patients and affected twins, the latter compared to their healthy co-twins. The population-based design enables the possibility of evaluating the validity of the CFS definition and, through molecular epidemiology, identify biological determinants of potential value for diagnosis.

Birgitta Evengård

The registry assesses twins aged 42 to 65 years old (n=31,406) for chronic fatigue from a telephone-based interview with the aim of identifying candidate twin pairs for further clinical, psychometric and biological sampling. To date, the team have collected and thoroughly reviewed all available medical records (n=2,489) for 1,779 individual twins with the strongest complaints of fatigue. Also, a web-based questionnaire for the age-group 18 to 42 years identified possibly discordant monozygotic twin pairs. In all, 33 pairs of monozygotic twin pairs discordant for CFS have been identified, and most have undergone medical examination, blood chemistry (sedimentation rate, white blood cell count, liver and renal function, thyroid hormones), serum proteomics, and screening of cerebrospinal fluid for molecular virus. In addition, mRNA-expression is under analysis as is the testing for virus and the cytokine array. To date, two known viruses have been detected in the cerebrospinal fluid through the molecular virus screening.

The preliminary results indicate little difference between affected and unaffected twins as regards age, education or occupation. Sleep difficulties, cognitive impairment, myalgia and joint pain seem to be the most common symptoms. Interestingly, oestrogen may be important, as expression of one of the oestrogen receptors was reduced in patients. In addition, an HPA axis disturbance has been observed.

Stephen Graves

In the final presentation of the day, Dr Stephen Graves (Director, Australian Rickettsial Reference Laboratory, New South Wales, Australia) shared with the audience his wide experience of “Q Fever” (Coxiella burnetii), “Flinders Island Spotted Fever” (Rickettsia honei strain marmionii) and their possible relationship to CFS. He explained that a period of fatigue after an infectious disease is a well-recognised phenomenon, which when it lasts for months and is referred to as “post-infectious chronic fatigue”. The Q-fever research group hypothesise that many cases of CFS are really “post-infectious chronic fatigue” and that a proportion of these cases are sequelae arising from Q Fever (infection with Coxiella burnetii) or Flinders Island Spotted Fever (infection with Rickettsia honei, strain marmionii). These two bacteria have an obligate, intracellular life style (as do viruses), passing between eukaryotic cells of vertebrates (bush mammals, reptiles, humans) and invertebrates (ticks). Post-typhus chronic fatigue Flinders Island Spotted Fever was first reported in Australia in 1940 but recent data (2008) shows the persistence of rickettsiae in peripheral blood mononuclear cells of affected patients.

Post-Q Fever chronic fatigue was first reported in Australia in 1996 and has now been confirmed by others. Antigen from C. burnetii persists in the patient’s bone marrow and peripheral blood mononuclear cells. The persistence of the microbial antigens in the patient appears to cause a dysregulation of the cytokine cascade leading to ongoing fatigue in a genetically predisposed subpopulation. If the group’s hypothesis is correct, public health measures to reduce rickettsial infections (e.g., by enhanced Q Fever immunisation) may have a positive impact on the incidence of CFS.

In a poster presentation accompanying the talk, Dr Graves with the Adelaide Q fever Research Group and collaborators explored further the issue of post-infection fatigue states of varying duration, which are familiar after viral, bacterial and protozoal infections. Of interest was a subgroup observed after infection with a range of obligate or facultative intra-cellular, or cell-dependent bacteria — especially the macrophage pathogens. During the period 1993 to the present, studies of Q fever yielded the following conclusions: that post-Q fever Fatigue Syndrome follows about 10 to 20% of clinically overt cases of acute primary Q fever and matches the standard CFS definitions; that patients with post-Q fever Fatigue Syndrome exhibit significant variant patterns of cytokine responses (IL-6, IFN gamma and IL-2) compared with various controls, when their peripheral blood mononuclear cells are stimulated with Q fever and control antigens in short term cell culture; that immunogenetic studies have shown significant frequency differences (i.e., gene polymorphisms), between post-Q fever Fatigue Syndrome on the one hand, and on the other hand, Q fever endocarditis, asymptomatic Q fever convalescents and unexposed population control panels. Overall, precipitating factors appear to be overt not subclinical infection (perhaps reflecting heavy seeding with coxiella components).

Our thanks go to Regina Clos for some of the photos of the day, and the complete selection of her photos, including of the beautiful town of Cambridge, can be found at her website CFS-aktuell. But our most grateful thanks go to the 130 delegates who came a long way to attend, and who — judging by the overwhelmingly positive feedback forms — found the experience educational and most importantly great fun!